title: Aflatoxin G1-induced oxidative stress causes DNA damage and triggers apoptosis through MAPK signaling pathway in A549 cells.
abstract: Our previous studies showed that Aflatoxin G1 (AFG1) could induce lung adenocarcinoma, and that the cancer cells originated from alveolar type II cells (AT-II cells). Recently, we found AFG1 induced structural impairment in rat AT-II cells, which may account for an early event in lung tumorigenesis. However, the mechanism of AFG1-induced AT-II cell damage remains unclear. DNA damage and apoptosis induced by oxidative stress are well accepted causes of cell damage. Thus, we explore whether AFG1 activates the reactive oxygen species (ROS)/MAPK/apoptosis pathway to cause cell damage in human AT-II cells like the cell line (A549). We found AFG1 induced oxidative stress by increasing ROS generation and caused DNA double-strand breaks (DSBs) by up-regulating γH2AX expression. AFG1 also triggered apoptosis in A549 cells by regulating Fas/FasL, caspase-8, Bax, Bcl-2, and activating caspase-3. Pre-treatment with antioxidant n-acetyl-l-cysteine (NAC) reduced ROS generation and DNA DSBs, inhibited apoptosis, and increased cell viability in AFG1-treated cells. Furthermore, we found AFG1 activated ROS-mediated JNK and p38 pathways to induce cell apoptosis in A549 cells. In conclusion, our results indicate that AFG1 induces oxidative DNA damage and triggers apoptosis through ROS-mediated JNK and p38 signaling pathways in A549 cells, which may contribute to AFG1-induced AT-II cell damage.
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongguang
authors.initials: H
authors.lastname: Lian
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xing
authors.forename: Xia
authors.initials: X
authors.lastname: Yan
authors.forename: Junling
authors.initials: J
authors.lastname: Wang
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000348:Aflatoxins / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000348:Aflatoxins; C494826:BAX protein, human; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C027955:aflatoxin G1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000111:Acetylcysteine
keywords: Aflatoxin; Alveolar type II cells; Apoptosis; Mitogen-activated protein kinases; Oxidative stress